Process for preparation of dronedarone by removal of hydroxyl group

ABSTRACT

The invention relates to a process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof characterized in that from the compound of formula (II). The hydroxyl group is removed, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Phase application under 35 U.S.C. §371 ofInternational Application No. PCT/HU2013/000010 filed Feb. 1, 2013 andclaims the benefit of EP Application No. EP12462004.8 filed Feb. 13,2012, the disclosures of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation ofdronedarone and pharmaceutically acceptable salts thereof, to novelintermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone is a known drug for the treatment of arrhythmia and has theChemical name ofN-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5-yl]methanesulfon-amide[see also formula (I) below]. There are some known processes for thepreparation of dronedarone as follows:

In EP 0471609 the following scheme is disclosed for the preparation ofdronedarone [Process A]

The above mentioned patent description discloses some new intermediarycompounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation ofdronedarone [Process B]:

The novelty of the process is based on the adaptation of theFriedel-Crafts reaction in the first step. The process and theintermediary compounds used for the preparation of the benzoylchloridecompound of the first step are also disclosed in this document. Thefurther steps of the process are identical with the final steps of thesynthetic route disclosed in EP 0471609 [Process A], but in the claimsthe whole synthetic route is claimed, up to dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed[Process C]. This method is the so-called superconvergent route. In thefirst step of it 5-amino-2-butylbenzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran inHCl salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reductionand the methansulforiylation steps are performed at the beginning of theprocedure. Besides the reaction route for preparation of dronedarone,the starting material 2-butyl-5-methansulfonamido-benzofuran and itspreparation is also claimed.

From among the mentioned procedures the first one [Process A] is theso-called linear synthesis. In this way of procedure the different partsof the dronedarone are stepwise built up on the starting compound. Thismethod is the least economical because the step by step building of thechemical groups is performed where more and more complicated andexpensive molecules are applied which rises the costs of preparation.Furthermore, it comprises complicated and dangerous reaction stepbecause aluminium chloride is used in the cleaving reaction of themethoxy group which makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed whichmakes this process more economical, but its last reaction step remained,the methansulfonylation reaction of the amino group. This reaction step(see the method described in example 6 of WO 02/48078) is complicatedand give a low yield, only 61.6%. Pure product can be obtained afterpurification using chromatographic column purification, which isnecessary because of the separation difficulties of thebis-methanesulfonylated product.

The process disclosed in WO 02/48132 (process C) is simpler and moreeconomical taken into consideration the number of the reaction steps.Unfortunately, in the last reaction step rather impure dronedarone.HCl(hydrochloride) is formed which is the obvious consequence of thepresence of dibutylamino group in the Friedel-Crafts reaction. Accordingto Examples 3 and 4, the crude dronedarone hydrochloride salt isprepared with a yield of 90% which was further purified and finally thecrude dronedarone base was produced with a yield of 86%. This base isreacted with hydrogen chloride gas dissolved in isopropanol whichresults in pure dronedarone hydrochloride salt. No yield was given forthis reaction step. According to example 5 crude dronedaronehydrochloride salt was prepared with a yield of 90%, which was washedwith water and reacted with hydrogen chloride gas dissolved inisopropanol, resulting dronedarone hydrochloride salt again. The qualityof this product is not known. However, neither the components used inthe Friedel-Crafts reaction nor the resulted products and by-productsare soluble in water, the washing step with water cannot result anypurification apart from the removal of inorganic salts.

It is an object of present invention to provide a novel process for thepreparation of dronedarone of formula (I). Starting with known andcommercially available materials, applying simple and environmentallycompatible reagents and solvents to afford high overall yields and goodpurity of the product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation ofdronedarone (I) and pharmaceutically acceptable salts thereof

wherein from the compound of formula (II)

the hydroxyl group is removed.

The present invention avoids the drawbacks of the procedures mentionedbefore, because formation of dronedarone in the final step is completedby removing the hydroxyl group next to the dibutylamine. This type ofreaction is advantageous because only little amounts of by-products areformed during the reduction process. The last step of the syntheticroute can be performed with a good yield using this type of reaction andthe purity of the product is also satisfactory. The reactants of thisreaction are not expensive and are widely used in the chemicallaboratory praxis.

Although removal of hydroxyl group from a compound is known in thechemical literature [Org. Synth. Coll. Vol. 1., 224 (1941); Jerry March:Advanced Organic Chemistry, Reactions, Mechanism and Structure, Chapter:Aliphatic Nucleofil Substitution, page 442 (4^(th) edition, John Wiley &Sons)] there is no common method to use for removal of a hydroxyl groupbeside a tertiary amino group. We found that the beta-hydroxyl group canbe removed with the described methods from the new compound of formula(II). The compound of formula (VII) is known from patent WO 02/48132(Sanofi). The compounds of formula (VIII) are known and can be purchasedfrom usual commercial sources.

Some intermediary compounds used in synthesis of dronedarone are new.Further aspects of the invention are the novel intermediary compoundsand the methods for the preparation thereof (see below in the “Detaileddescription of the invention” part). The applied other startingmaterials are available from commercial sources.

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparationof dronedarone and pharmaceutically acceptable salts thereof. The wholeprocess—starting from compounds available commercial sources—reads asfollows:

A) For the preparation of compound of formula (V)

the compound of formula (VII)

is reacted with a compound of formula (VIII)

where X is halogen, typically chlorine.

The reaction is carried out in a solvent or mixture of inert solvents,typically in the presence of base. The solvent can be selected from thegroup of C1-C4 alcohols (e.g. ethanol or isopropyl alcohol), ketones(e.g. methylethyl ketone) and acetonitril and mixtures thereof.

The base (applied for acid binding) can be selected from group ofinorganic bases [e.g. carbonates, hydrogen carbonates (typically alkalicarbonates), alkali hydroxides].

The temperature is typically between 50-120° C.

B) For the preparation of compound of formula (IV)

the compound of formula (V)

is reacted with the amine of formula (VI)

Typically the reaction is carried out in a solvent. The solvent can beselected from the group C1-C4 alcohols, ethyl acetate andtetrahydrofurane and mixtures thereof (e.g. propanol or ethanol,especially propanol, e.g. isopropanol).

The temperature is typically between 50-120° C.

C) For the preparation of compound of formula (III) and pharmaceuticallyacceptable salts thereof

the compound of formula (IV)

is hydrogenated.

The hydrogenation of compound of formula (IV) is carried out in asolvent or mixture of solvents, in the presence of a catalyst, which canbe e.g. PtO₂ or Pd/C. The solvent can be selected from the group C1-C4alcohols, ethyl acetate, cyclohexane and tetrahydrofurane and mixturesthereof (e.g. ethanol or methanol).

D) For the preparation of compound of formula (II) and pharmaceuticallyacceptable salts thereof,

the compound of formula (III)

is mesylated.

The mesylation is carried out in a solvent or mixture of inert solvents,typically in the presence of base. The solvent can be selected from thegroup of halogenated solvents (e.g. dichloromethane, dichloroethane,chlorobenzene), aromatic solvents (e.g. toluene) and ethers (e.g.diisopropyl ether) and mixtures thereof. The base can be selected fromgroup of tertiary amines (e.g. pyridine or triethyl amine) and inorganicbases (e.g carbonates, hydrogen carbonates, alkali hydroxides). In theprocess a mesylating reagent should be applied. It can be any reagentwhich can be used for inserting a CH₃SO₂— group into the free aminogroup of compound of formula (III). It is practical to usemethanesulfonic anhydride or methanesulfonyl halogenide, e.g.methanesulfonyl chloride.

E) Finally, for the preparation of dronedarone of formula (I) andpharmaceutically acceptable salts thereof

from the compound of formula (II)

the hydroxyl group is removed.

The removal of hydroxyl group can be carried out by any usable methodknown in the chemical literature, as it was discussed at the end of theSummary of the Invention part.

For example, the reaction is carried out with reagent(s) selected fromthe following groups:

a) hydrogen iodide and phosphorous acid (H₃PO₃),

b) dialkyl silane and boron trifluoride,

c) sodium iodide and dihalogen(dialkyl)silane, e.g. dichlorodimethylsilane,

d) iodotrimethyl silane,

e) sodium borohydride and trifluoacetic acid,

f) phosphorus and iodine.

In a typical method the reaction is carried out with hydrogen iodide andphosphorous acid in acetic acid as solvent.

In another typical method the reaction is carried out with sodium iodideand dichlorodimethyl silane in acetonitrile as solvent.

As used herein, the term alkyl includes straight or branched aliphatichydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl,isopropyl and t-butyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo andiodo atoms.

In the above reactions the temperature is chosen according to thegeneral practice of a person skilled in organic chemistry. Typically thetemperature is between 10° C. and the boiling point of the appliedsolvent (which can be the mixture of the mentioned solvents in aspecific embodiment). Applicable temperature values can be found in theexamples.

All the above reactions are carried out under atmospheric pressure withthe exception of the hydrogenation steps where higher pressure also canbe applied, typically up to 20 bar, e.g. 5 to 10 bar. Applicablepressure values can be found in the examples.

The applicable acid for the preparation of pharmaceutically acceptablesalts can be any inorganic or organic acid which forms an acid additionsalt with the compound of general formula (I). Exemplary acids which canform an acid addition salt are as follows: acetic acid, adipic acid,alginic acid, ascorbic acid, aspartic acid, benzoic acid,benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boricacid, butyric acid, citric acid, fumaric acid, hydrogen chloride,hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonic acid, maleicacid, oxalic acid, nitric acid, salicylic acid, tartaric acid, sulfuricacid (forming sulfate or bisulfate anion), sulfonic acid (such as thosementioned herein), succinic acid, toluenesulfonic acid and the like. Thehydrogen halogenide salts are typical, especially the hydrogen chloridesalt.

Here it is mentioned that on the mesylate group of compound of generalformula (I) (see the “left side” of the molecule) a salt formation canbe carried out (on the amide part of it) by a strong base, e.g. analkaline hydroxide, typically by sodium hydroxide. However, these saltshave less practical. importance, but they are within the scope of salts.It means that the phrase “salts” embraces both the acid addition saltsand the salts formed by bases (basic salts) in case of compounds ofgeneral formula (I).

As it was mentioned above the further starting materials arecommercially available or can be prepared by applying known syntheticways, e.g. as it is given in the relating examples.

Other objects of the invention are the novel intermediary compoundsapplied in the processes, namely the following compounds:

-   -   The compound of formula (II) and pharmaceutically acceptable        salts thereof

-   -   The compound of formula (III) and pharmaceutically acceptable        salts thereof

-   -   The compound of formula (IV) and pharmaceutically acceptable        salts thereof

-   -   The compound of formula (V)

In the processes for the preparation of the intermediary compounds theproduct is isolated as a base typically (if the compound has analkylated amino group). If desired, the isolated base can be convertedinto a salt (acid addition salt) thereof, which is typically apharmaceutically acceptable salt [the possible acids are mentioned inpoint E)]. Theoretically the acid addition salt can be prepared directlyif the relating acid is in the final reaction mixture from which thesolid product is made (however, this way is not applied in case of thesecompounds where the base type form has practical importance).

Here it is mentioned that the above intermediary compound of formula(II) has a mesylate group (see the “left side” of the molecules) where asalt formation can be carried out (on the amide part of it) by a strongbase, e.g. an alkaline hydroxide, typically by sodium hydroxide.However, these salts have less practical importance, but they are withinthe scope of salts which can be prepared by the claimed process, i.e.the phrase “salts” embraces the salts formed by bases (basic salts) insuch cases (where the molecule has a mesylate group).

EXAMPLES

The solutions where the solvent is not defined are aqueous solutions inall the examples.

Example 1N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide(I)

0.5 g ofN-(2-butyl-3-(4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-Ibenzofuran-5-yl)methanesulfonamide(II) 0.1 g of phosphorous acid (H₃PO₃) of 99% and 0.05 g of aqueoushydrogen iodide solution of 57% was dissolved in 5 ml of acetic acid.The mixture was warmed at 60° C. for 1 hour and at 80° C. for 4 hours.The mixture was cooled to 25° C. and diluted with 10 ml of water. The pHwas set to pH=7 using diluted sodium hydroxide. The mixture wasextracted with 2×5 ml of dichloromethane. The dichloromethane was washedwith 2×5 ml of water and evaporated.

Mass of product 0.48 g (98%). The product was purified by columnchromatography on silica gel (eluent: ethyl acetate/hexane 1:3 v/v).

Mass of purified product: 0.44 g (90%).

Purity (HPLC): 99.44%.

1H NMR (DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 (m, 10H); 1.67 (5′, 2H);1.87 (5′, 2H); 2.38 (t, J=7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J=7.5 Hz,2H); 2.91 (s, 3H); 4.15 (t, J=6.2 Hz, 2H); 7.09 (d, J=8.8 Hz, 2H); 7.24(dd, J=8.9, 2.2 Hz, 1H); 7.34 (d, J=2.1 Hz, 1H); 7.65 (d, J=8.8 Hz, 1H);7.81 (d, J=8.8 Hz, 2H).

Example 2N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide(I)

0.8 g ofN-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)methanesulfonamide(II) was dissolved in 2 ml of acetonitrile and 0.9 g of sodium iodidewas added. Under stirring at 25° C. 0.2 g of dichlorodimethylsilane wasadded: After stirring for 15 Min the mixture was diluted with 5 ml ofethyl acetate and washed with 5 ml of water, with 5 ml of sodiumhydrocarbonate solution of 5%, with sodium thiosulfate solution of 10%and with water. The solvent was evaporated. Mass of product 0.8 g.

The product is purified by forming its oxalate salt as follows: to theresidue 4 ml of methylethyl ketone is added and the mixture heated to70. To this solution 0.17 g of oxalic acid dissolved in 1.5 ml ofmethylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hoursthe mixture is stirred at 10° C. for 1 hour and filtered. To theobtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and0.46 g of potassium carbonate are added. After stirring for 30 minutesthe separated potassium oxalate is filtered and washed with 2 ml ofdichloromethane and the solvent is evaporated.

Mass of purified product 0.75 g (92%).

Purify (HPLC): 98.9%.

The product was identical with compound prepared in example 1.

Example 3N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)-methane-sulfonamide(II)

0.3 g of (5-amino-2-butyl-1-benzofuran-3-yl){4-[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone (III) wasdissolved in 10 ml of dichloromethane. The solution was warmed to 30-35°C. and 0.06 g of pyridine was added at this temperature. After this0.093 g of methanesulfonyl chloride was added and the mixture wasstirred at 30-35° C. for 2 hours. The mixture was cooled to 20-25° C.,washed with 2×15 ml of water, 2×15 ml of sodium hydrogencarbonatesolution of 5%, 1×15 ml of water. The phases were sepatated and thedichloromethane phase was evaporated.

Mass of product: 0.32 g (94.1%).

Purity (HPLC): 78.9%.

[M-H]⁺ _(measured)=573.3 Da.

[M-H]⁺ _(calculated)=573.3 Da.

1H NMR (DMSO): δ ppm 0.78-0.87 (m, 9H) 1.18-1.31 (m, 6H) 1.33-1.44 (m,4H) 1.65 (quin, J=7.30 Hz, 2H) 2.28-2.49 (m, 5H) 2.59-2.68 (m, 1H) 2.79(t, J=7.32 Hz, 2H) 2.89 (s, 3H) 3.86 (br. S, 1H) 3.97-4.06 (m, 1H) 4.12(dd, J=9.84, 3.43 Hz, 1H) 7.08 (d, J=8.93 Hz, 2H) 7.22 (dd, J=8.81, 2.17Hz, 1H) 7.32 (d, J=1.83 Hz, 1H) 7.62 (d, J=8.70 Hz, 1H) 7.79 (d, J=8.70Hz, 2H).

Example 4 5-amino-2-butyl-1-benzofuran-3-yl){4-[3-(dibutylamino)-2-hydroxypropoxy]-phenyl}-methanone (III

2.2 g of(2-butyl-5-nitro-1-benzofuran-3-yl){[3-(dibutylamino)-2-hydroxypropoxy]-phenyl}ethanone(IV) was dissolved in 32 ml of methanol and 0.7 g of Pd/C catalyst of 5%was added. The mixture was set under hydrogen pressure of 10 bar andstirred at 25° C. for 90 min. The catalyst was filtered off and thesolution was evaporated.

Mass of product: 1.9 g (92.7%).

Purity (HPLC): 92.1%.

[M-H]⁺ _(measured)=495.3 Da.

[M-H]⁺ _(calculated)=495.3 Da.

1H NMR (DMSO): δ ppm 0.80 (t, J=7.30 Hz, 3H) 0.83 (t, J=7.32 Hz, 6H)1.23-1.28 (m, 6H) 1.34-1.37 (m, 4H) 1.62 (quin, J=7.50 Hz, 2H) 2.34-2.42(m, 5H) 2.5′8 (dd, J=13.05, 7.55 Hz, 1H) 2.71 (t, J=7.55 Hz, 2H)3.84-3.92 (m, 1H) 3.99 (dd, J=9.84, 5.72 Hz, 1H) 4.11 (dd, J=9.96, 3.09Hz, 1H) 6.53 (d, J=2.06 Hz, 1H) 6.58 (dd, J=8.70, 2.29 Hz, 1H) 7.07 (d,J=8.70 Hz, 2H) 7.26 (d, J=8.70 Hz, 1H) 7.75 (d, j=8.93 Hz, 2H).

Example 52-butyl-5-nitro-1-benzofuran-3-yl){[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone(IV

1.4 g of(2-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]-methanone(V) was dissolved in 10 ml of isopropanol. 2.74 g of dibutylamin wasadded and the mixture was boiled for 4 hours. The mixture wasevaporated.

Mass of product: 1.88 g (100%).

Purity (HPLC): 92.0%.

[M-H]⁺ _(measured)=525.3 Da.

[M-H]⁺ _(calculated)=525.3 Da.

1H NMR (DMSO): 0.78-0.84 ppm (m, 9H); 1.20-1.29 (m, 6H); 1.30-1.38 (m,4H); 1.68 (quin, J=7.5 Hz, 2H); 2.37-2.46 (m, 5H); 2.58 (dd, J=13.05,7.78 Hz, 1H); 2.84 (t, J=7.55 Hz, 2H); 3.85-3.91 (m, 1H); 4.02 (dd,J=9.96, 5.61 Hz, 1H); 4.13 (dd, J=9.84, 3.20 Hz, 1H); 7.10 (d, J=8.93Hz, 2H); 7.82 (d, J=8.93 Hz, 2H); 7.92 (d, J=8.24 Hz, 1H); 8.23-8.28 (m,2H).

Example 6 2-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]methanone (V

5 g of (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxy-phenyl)methanone(VII) was dissolved in 30 ml of acetonitrile and 6.1 g of potassiumcarbonate, 6.6 g of sodium iodide and 4.0 g of epichlorohydrin wereadded. The mixture was boiled for 6 hours and cooled down. The solid wasfiltered off and the solution was evaporated.

Mass of product: 5.9 g (101%).

Purity (HPLC): 87.9%.

[M-H]⁺ _(measured)=396.1 Da.

[M-H]⁺ _(calculated)=396.1 Da.

1H NMR (DMSO): 0.81 ppm (t, J=7.32 Hz, 3H); 1.25 (sxt, J=7.30 Hz, 2H);1.68 (quin, J=7.44 Hz, 2H); 2.75 (dd; J=5.04, 2.52 Hz, 1H); 2.84 (t,J=7.55 Hz, 2H); 2.86-2.89 (m, 1H); 3.33-3.39 (m, 1H); 3.94-4.00 (m, 1H);4.49 (dd, J=11.22, 2.75 Hz, 1H); 7.10-7.18 (m, 2H); 7.83 (dd, J=8.70,2.75 Hz, 1H); 7.92 (d, J=9.84 Hz, 1H); 8.22-8.28 (m, 2H).

Example 72-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]methanone(V

5 g of (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxy-phenyl)methanone(VII) was dissolved in 50 ml of isopropanol and 0.625 g of solid sodiumhydroxide was added. The mixture was stirred at room temperature for 10min and 2.5 g of epibromohydrine (VIII) (Aldrich) was added. The mixturewas boiled for 90 min and evaporated at 40° C. 15 ml of water of 0° C.was added and 30 ml of dichloromethane. The phases were separated after10 min of stirring. The dichloromethane was evaporated.

Mass of product: 5.85 g (100%).

Purity (HPLC): 90.1%.

[M-H]⁺ _(measured)=396.1 Da.

[M-H]⁺ _(calculated)=396.1 Da.

The product was identical with compound prepared in example 6.

The invention claimed is:
 1. A process for the preparation ofdronedarone (I), or a pharmaceutically acceptable salt thereof,

comprising the steps of: a) reacting the compound of formula (II)

to remove the hydroxyl group; b) isolating dronedarone (I); and c)optionally converting dronedarone (I) into a pharmaceutically acceptablesalt thereof.
 2. The process of claim 1, wherein the reaction to removethe hydroxyl group is carried out with reagent(s) selected from thegroup consisting of: a) hydrogen iodide and phosphorous acid, b) dialkylsilane and boron trifluoride, c) sodium iodide anddihalogen(dialkyl)silane, d) iodotrimethyl silane, e) sodium borohydrideand trifluoacetic acid, and f) phosphorus and iodine.
 3. The process ofclaim 2, wherein the reaction is carried out with hydrogen iodide andphosphorous acid in acetic acid as solvent.
 4. The process of claim 2,wherein the reaction is carried out with sodium iodide anddichlorodimethyl silane in acetonitrile as solvent.
 5. The process ofclaim 1 further comprising a process for the preparation of the compoundof formula (II)

wherein: a compound of formula (VII)

is reacted with a compound of formula (VIII)

to obtain a compound of formula (V)

the obtained compound of formula (V) is reacted with an amine of formula(VI)

to obtain a compound of formula (IV)

the obtained compound of formula (IV) is hydrogenated to obtain acompound of formula (III)

the obtained compound of formula (III) is mesylated to obtain thecompound of formula (II).
 6. The process of claim 5, wherein thereaction of step a) is carried out with reagent(s) selected from thegroup consisting of: a) hydrogen iodide and phosphorous acid, b) dialkylsilane and boron trifluoride, c) sodium iodide anddihalogen(dialkyl)silane, d) iodotrimethyl silane, e) sodium borohydrideand trifluoacetic acid, and f) phosphorus and iodine.
 7. The process ofclaim 6, wherein the reaction of step a) is carried out with hydrogeniodide and phosphorous acid in acetic acid as solvent.
 8. The process ofclaim 6, wherein the reaction of step a) is carried out with sodiumiodide and dichlorodimethyl silane in acetonitrile as solvent.